dbSNP rs9869263: CLDN1:p.Gly123Gly (chr3-190312891-A-G) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021101.5(CLDN1):c.369T>C(p.Gly123Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.838 in 1,613,742 control chromosomes in the GnomAD database, including 567,397 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.82 ( 51537 hom., cov: 31)

Exomes 𝑓: 0.84 ( 515860 hom. )

Consequence

CLDN1
NM_021101.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -7.62

Publications

29 publications found

Variant links:

Genes affected

CLDN1 (HGNC:2032): (claudin 1) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. Loss of function mutations result in neonatal ichthyosis-sclerosing cholangitis syndrome. [provided by RefSeq, Jul 2008]

CLDN1 links:

CLDN16 (HGNC:2037): (claudin 16) Tight junctions represent one mode of cell-to-cell adhesion in epithelial or endothelial cell sheets, forming continuous seals around cells and serving as a physical barrier to prevent solutes and water from passing freely through the paracellular space. These junctions are comprised of sets of continuous networking strands in the outwardly facing cytoplasmic leaflet, with complementary grooves in the inwardly facing extracytoplasmic leaflet. The protein encoded by this gene, a member of the claudin family, is an integral membrane protein and a component of tight junction strands. It is found primarily in the kidneys, specifically in the thick ascending limb of Henle, where it acts as either an intercellular pore or ion concentration sensor to regulate the paracellular resorption of magnesium ions. Defects in this gene are a cause of primary hypomagnesemia, which is characterized by massive renal magnesium wasting with hypomagnesemia and hypercalciuria, resulting in nephrocalcinosis and renal failure. This gene and the CLDN1 gene are clustered on chromosome 3q28. [provided by RefSeq, Jun 2010]

CLDN16 links:

P3H2-AS1 (HGNC:40886): (P3H2 antisense RNA 1)

P3H2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP6

Variant 3-190312891-A-G is Benign according to our data. Variant chr3-190312891-A-G is described in ClinVar as Benign. ClinVar VariationId is 195367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-7.62 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.839 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021101.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN1	NM_021101.5	MANE Select	c.369T>C	p.Gly123Gly	synonymous	Exon 2 of 4	NP_066924.1	O95832
CLDN16	NM_001378492.1		c.-445-2002A>G		intron	N/A	NP_001365421.1	Q9Y5I7
CLDN16	NM_001378493.1		c.-279+22300A>G		intron	N/A	NP_001365422.1	Q9Y5I7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CLDN1	ENST00000295522.4	TSL:1 MANE Select	c.369T>C	p.Gly123Gly	synonymous	Exon 2 of 4	ENSP00000295522.3	O95832
CLDN1	ENST00000490800.1	TSL:2	n.328T>C		non_coding_transcript_exon	Exon 1 of 2
P3H2-AS1	ENST00000747181.1		n.627-2002A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.823

AC:

125001

AN:

151954

Hom.:

51503

Cov.:

show subpopulations

Gnomad AFR

AF:

0.770

Gnomad AMI

AF:

0.814

Gnomad AMR

AF:

0.811

Gnomad ASJ

AF:

0.862

Gnomad EAS

AF:

0.833

Gnomad SAS

AF:

0.827

Gnomad FIN

AF:

0.879

Gnomad MID

AF:

0.927

Gnomad NFE

AF:

0.845

Gnomad OTH

AF:

0.823

GnomAD2 exomes

AF:

0.832

AC:

209149

AN:

251432

AF XY:

0.836

show subpopulations

Gnomad AFR exome

AF:

0.769

Gnomad AMR exome

AF:

0.784

Gnomad ASJ exome

AF:

0.864

Gnomad EAS exome

AF:

0.823

Gnomad FIN exome

AF:

0.869

Gnomad NFE exome

AF:

0.848

Gnomad OTH exome

AF:

0.839

GnomAD4 exome

AF:

0.840

AC:

1227389

AN:

1461670

Hom.:

515860

Cov.:

AF XY:

0.840

AC XY:

610604

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.769

AC:

25724

AN:

33464

American (AMR)

AF:

0.783

AC:

34991

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.866

AC:

22639

AN:

26132

East Asian (EAS)

AF:

0.850

AC:

33760

AN:

39698

South Asian (SAS)

AF:

0.822

AC:

70925

AN:

86252

European-Finnish (FIN)

AF:

0.871

AC:

46524

AN:

53408

Middle Eastern (MID)

AF:

0.862

AC:

4972

AN:

5768

European-Non Finnish (NFE)

AF:

0.843

AC:

937253

AN:

1111846

Other (OTH)

AF:

0.838

AC:

50601

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

10808

21616

32425

43233

54041

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21112

42224

63336

84448

105560

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.823

AC:

125089

AN:

152072

Hom.:

51537

Cov.:

AF XY:

0.825

AC XY:

61361

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.770

AC:

31912

AN:

41450

American (AMR)

AF:

0.811

AC:

12387

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.862

AC:

2992

AN:

3470

East Asian (EAS)

AF:

0.833

AC:

4301

AN:

5162

South Asian (SAS)

AF:

0.828

AC:

3984

AN:

4814

European-Finnish (FIN)

AF:

0.879

AC:

9312

AN:

10596

Middle Eastern (MID)

AF:

0.922

AC:

271

AN:

294

European-Non Finnish (NFE)

AF:

0.845

AC:

57461

AN:

67988

Other (OTH)

AF:

0.818

AC:

1727

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1142

2283

3425

4566

5708

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

882

1764

2646

3528

4410

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.836

Hom.:

154884

Bravo

AF:

0.814

Asia WGS

AF:

0.800

AC:

2785

AN:

3478

EpiCase

AF:

0.846

EpiControl

AF:

0.851

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

Neonatal ichthyosis-sclerosing cholangitis syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.037

(source)

DANN

Benign

0.72

PhyloP100

-7.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over